Ubiquitin-Proteasome System: Key Insights into Neurological Disorder Mechanisms

Abstract:: The ubiquitin-proteasome system (UPS) is crucial for maintaining protein homeostasis in the central nervous system. Dysfunction of the UPS leads to the accumulation of neurotoxic aggregates, including amyloid, tau, alpha-synuclein, SOD1, and TDP-43, which are hallmark features of various neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. Agerelated decline in the UPS and autophagy-lysosomal pathways results in compromised proteostasis and progressive neuronal damage. Current literature from diverse databases provides insights emphasizing the clinical relevance of UPS-targeted interventions. Strategies such as targeted degradation of misfolded proteins, modulation of PINK1/Parkin-mediated mitophagy, and the use of enzyme activators or allosteric modulators show potential in restoring brain homeostasis. This review discusses UPS-mediated proteolytic mechanisms, molecular disruptions associated with disease progression, and emerging therapeutic approaches aimed at enhancing protein clearance.